S106: UBTF-ATXN7L3 GENE FUSION DUE TO 17Q21.31 DELETION DEFINES NOVEL HIGH-RISK ALL SUBTYPE AMENABLE TO MRD-BASED TREATMENT INTENSIFICATION
Authors: L. Bastian, A. Hartmann, T. Beder, S. Hänzelmann, J. Kässens, M. Bultmann, M. P. Höppner, S. Franzenburg, M. Wittig, A. Franke, I. Nagel, M. Spielmann, N. Reimer, H. Busch, S. Schwartz, B. Steffen, A. Viardot, K. Döhner, M. Kondakci, G. Wulf, K. Wendelin, A. Renzelmann, A. Kiani, H. Trautmann, M. Neumann, N. Gökbuget, M. Brüggemann, C. Baldus
Journal: HemaSphere (2022)

Background: Response to induction chemotherapy assessed by quantification of minimal residual disease (MRD) is the strongest independent prognosticator in B precursor acute lymphoblastic leukemia (BCP-ALL). Molecular underpinnings of MRD poor response are insufficiently understood. Aims: We aimed to identify novel high-risk subtypes in adult BCP-ALL as cell-intrinsic determinants of MRD poor response. Methods: Adult BCP-ALL patients (n=565) were treated according to pediatric inspired protocols of the German Acute Lymphoblastic Leukemia Study group (GMALL) and profiled for integrative analyses by RNA-Seq (n=565), SNP-arrays (n=115), whole exome sequencing (WES; n=84) and whole genome sequencing (WGS; n=3). Results: Concordance between transcriptomic and genomic profiles was used to allocate samples to one of 15 established molecular driver subgroups (Figure A). Unsupervised clustering of gene expression from the remaining samples revealed a distinct cluster (n=12/565, 2.1%) with an in-frame gene fusion between upstream binding transcription factor (UBTF) and ataxin-7-like protein 3 (ATXN7L3) as exclusive event in these patients. Both fusion partners are in direct neighborship at 17q21.31. WGS revealed a 10.08 kb genomic deletion which truncated UBTF at exon 17/21 and comprised most of the intergenic region between both genes (Figure B). UBTF-ATXN7L3 rearranged cases frequently harbored 1q gains (n=5/7). Further genomic profiling showed a remarkable paucity of additional cooperating events compared to other molecular subtypes, supporting a prominent driver function of the newly identified fusion. UBTF and ATXN7L3 are global epigenetic regulators involved in transcriptional control. Both genes were highly expressed across the entire cohort. The gene fusion was associated with a marked increase of Caudal Homeobox 2 (CDX2) expression. Analysis of functional modules related CDX2 to upregulated HOXA9 and MEIS1, described essential co-regulators of KMT2A-driven leukemogenesis. NTRK3 expression was also strongly upregulated, suggesting a possible rationale for specific inhibitors. UBTF-AXTN7L3 rearranged patients were older, more frequently female and presented with normal leukocyte counts, low bone marrow infiltration and pro-B immunophenotypes or common ALL with reduced CD10 expression. Response to induction chemotherapy in evaluable patients (n=11) was poor with only 3 patients achieving MRD negativity after consolidation I compared to n=271/402 (67%; p=0.019) in the remaining cohort. Four patients suffered either cytologic (n=2) or molecular (n=2) relapse. Immunotherapeutic treatment intensification using blinatumomab (n=5) or inotuzumab ozogamizin (n=1) and / or allogenic stem cell transplantation (n=7) in MRD poor responders or relapsed cases resulted in an overall survival probability of 80% (+/- 12%) vs. 73% (+/- 2%; p=0.07) in the remaining cohort. Heterogeneous MRD responses were observed for other molecular subtypes (poor: ZNF384 - 48.2% MRD neg., p=0.056; Ph-like - 54.0% MRD neg., p=0.003; KMT2A - 55.8% MRD neg., p=0.127 / good: High Hyperdiploid - 90.9% MRD neg., p=0.01; TCF3-PBX1 - 94.1% MRD neg., p=0.016) indicating how molecular drivers affect chemo-sensitivity in adult BCP-ALL. Image:Summary/Conclusion: Molecular driver alterations determine sensitivity to induction chemotherapy in adult BCP-ALL. UBTF-ATXN7L3 ALL represents a novel subtype with poor induction chemotherapy response which could be successfully salvaged by MRD-based treatment intensification using immunotherapeutic strategies.